Min Hong Ki, Lee Ji-Yeon, Lee Sang-Heon, Kim Hae-Rim
Division of Rheumatology, Department of Internal Medicine, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Republic of Korea.
The Rheumatism Research Center, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Republic of Korea.
Clin Exp Rheumatol. 2025 Jan;43(1):34-40. doi: 10.55563/clinexprheumatol/zf6zct. Epub 2024 Jul 25.
Mast cell activation induces pathological responses, including increased osteoclastogenesis in rheumatoid arthritis (RA). Interleukin (IL)-18 binding protein (IL-18BP) has anti-inflammatory effects. In this study, we evaluated the effect of IL-18BP on mast cell activation and mast cell induced osteoclastogenesis.
Mast cells were activated by IL-33 (100 ng/mL) and cultured with IL-18BP (10, 50, and 100 ng/mL). The proliferation, apoptosis, and necroptosis of mast cells were measured using flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of mast cell enzymes, matrix metalloproteinase (MMP), soluble RANKL (sRANKL), and pro-inflammatory cytokines in the culture media. Monocytes from patients with RA patients (n=5) were cultured with activated mast cells with various concentrations of IL-18BP. TRAP+ multinucleated osteoclasts, bone resorption area, and osteoclast differentiation-related genes were measured.
Proliferation of tryptase+chymase+c-kit+FcεR1+ mast cells was suppressed following incubation with IL-18BP (10, 50, and 100 ng/mL). RNA expression levels of tryptase and chymase were reduced by 100 ng/mL IL-18BP. Additionally, the levels of MMP-3/9, IL-17A, IL-6, TNF-α, and sRANKL were significantly inhibited by 100 ng/mL IL-18BP. Annexin V+ and annexin V-PI+ mast cells were reduced following incubation with 100 ng/mL IL-18BP. The addition of IL-33 significantly stimulated mast cell and increased TRAP+ multinucleated cells and bone resorption area, and these effects were suppressed by IL-18BP. The osteoclast-related genes (TRAP, ATP6v0d2, RANK, and cathepsin K) expression were suppressed by IL-18BP.
IL-18BP suppressed mast cell activation and mast cell induced osteoclastogenesis. This suggests a potential anti-arthritic role for IL-18BP in patients with RA.
肥大细胞活化会引发病理反应，包括类风湿关节炎（RA）中破骨细胞生成增加。白细胞介素（IL）-18结合蛋白（IL-18BP）具有抗炎作用。在本研究中，我们评估了IL-18BP对肥大细胞活化以及肥大细胞诱导的破骨细胞生成的影响。
用IL-33（100 ng/mL）激活肥大细胞，并与IL-18BP（10、50和100 ng/mL）共同培养。使用流式细胞术检测肥大细胞的增殖、凋亡和坏死性凋亡。采用酶联免疫吸附测定（ELISA）法检测培养基中肥大细胞酶、基质金属蛋白酶（MMP）、可溶性RANKL（sRANKL）和促炎细胞因子的水平。将类风湿关节炎患者（n = 5）的单核细胞与不同浓度IL-18BP的活化肥大细胞共同培养。检测抗酒石酸酸性磷酸酶（TRAP）阳性多核破骨细胞、骨吸收面积以及破骨细胞分化相关基因。
用IL-18BP（10、50和100 ng/mL）孵育后，类胰蛋白酶+糜蛋白酶+c-kit+FcεR1+肥大细胞的增殖受到抑制。100 ng/mL IL-18BP可降低类胰蛋白酶和糜蛋白酶的RNA表达水平。此外，100 ng/mL IL-18BP可显著抑制MMP-3/9、IL-17A、IL-6、肿瘤坏死因子-α（TNF-α）和sRANKL的水平。用100 ng/mL IL-18BP孵育后，膜联蛋白V+和膜联蛋白V-碘化丙啶+肥大细胞减少。添加IL-33可显著刺激肥大细胞并增加TRAP阳性多核细胞和骨吸收面积，而这些作用被IL-18BP抑制。IL-18BP可抑制破骨细胞相关基因（TRAP、ATP6v0d2、RANK和组织蛋白酶K）的表达。
IL-18BP可抑制肥大细胞活化以及肥大细胞诱导的破骨细胞生成。这表明IL-18BP在类风湿关节炎患者中可能具有潜在的抗关节炎作用。
